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Eckenweber, Florian; Medina-Luque, Jose; Blume, Tanja; Sacher, Christian; Biechele, Gloria; Wind, Karin; Deussing, Maximilian; Briel, Nils; Lindner, Simon; Boening, Guido; Ungern-Sternberg, Barbara von; Unterrainer, Marcus; Albert, Nathalie L. ORCID: 0000-0003-0953-7624; Zwergal, Andreas; Levin, Johannes; Bartenstein, Peter; Cumming, Paul; Rominger, Axel; Höglinger, Günter U.; Herms, Jochen; Brendel, Matthias (2020): Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning. In: Journal of Neuroinflammation, Vol. 17, No. 1, 208
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Abstract

Background: P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in the brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18 kDa translocator protein positron-emission-tomography (TSPO mu PET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism. Methods Transgenic P301S (n= 33) and wild-type (n= 18) female mice were imaged by(18)F-GE-180 TSPO mu PET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze,F-18-fluordesoxyglucose (F-18-FDG) mu PET, and AT8 tau immunohistochemistry at 6.3-6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO mu PET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-beta mouse models. Results TSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+ 11-23%, allp< 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-beta mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3-6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.3-6.7 months. Conclusions: Monitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by mu PET indicates a delayed time course when compared to amyloid-beta mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-beta mouse models. The contribution of microglial response to pathology accompanying amyloid-beta and tau over-expression merits further investigation.